Mervometostat

Shows activity

Also known as:

EZH2i PF-06821497

Cancer types include:

non-small cell lung cancer prostate cancer small cell lung cancer

HealthScout AI Analysis

Show HealthScout AI Analysis

Overview

Mervometostat (also spelled Mevrometostat; development code PF-06821497) is an oral, selective inhibitor of the histone methyltransferase EZH2 under clinical evaluation, most prominently in metastatic castration‑resistant prostate cancer (mCRPC), including randomized dose‑expansion data and an ongoing phase 3 trial in combination with enzalutamide. Preclinical chemistry and target engagement for PF‑06821497 have been published, and multiple ASCO meeting abstracts have reported early clinical efficacy and safety signals. (pubs.acs.org)

Mechanism of action

Target: EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2) that trimethylates H3K27 and represses gene transcription. PF‑06821497 is a potent, SAM‑competitive EZH2 inhibitor discovered via ligand/property‑based design. In biochemical assays it shows sub‑nanomolar potency and reduces H3K27me3, leading to re‑expression of EZH2‑repressed genes. (pubs.acs.org)
Pharmacodynamic evidence in patients: In mCRPC biopsies and blood, mervometostat plus enzalutamide produced dose‑dependent reductions in H3K27Me3; at 1250 mg BID, mean tumor H3K27Me3 decreased ~67–75% with accompanying gene‑expression changes consistent with PRC2/EZH2 inhibition. (ascopubs.org)

Efficacy

Phase 1/2 (dose escalation; mCRPC, combo with enzalutamide): In 47 patients (data cut Nov 2, 2023), median radiographic PFS was 17.0 months overall; confirmed PSA50 responses in 14.9%; among 22 patients with measurable disease, ORR was 27.3% (including 1 CR and 5 PRs). Durable activity was seen across prior abiraterone/enzalutamide exposure cohorts. (ascopubs.org)
Phase 1 randomized dose‑expansion (mCRPC, prior abiraterone; mervometostat 1250 mg BID + enzalutamide vs enzalutamide): As of Sept 2, 2024 (n=81), median rPFS was 14.3 months with the combination vs 6.2 months with enzalutamide alone (HR 0.51; 90% CI 0.28–0.95). In patients with measurable disease at baseline, ORR was 26.7% vs 14.3%; confirmed PSA50 responses occurred in 34.1% vs 15.4%, respectively. (ascopubs.org)
Phase 3 (MEVPRO‑2; ongoing): A global, double‑blind randomized trial in ARPI‑naïve mCRPC comparing mervometostat 875 mg BID + enzalutamide vs placebo + enzalutamide; primary endpoint is blinded independent review–assessed rPFS. (ascopubs.org)

Note: The foundational phase 1/2 program (NCT03460977) also included follicular lymphoma and small‑cell lung cancer cohorts; public efficacy details to date are concentrated in the mCRPC combination setting. (ascopubs.org)

Safety

In phase 1 dose escalation (mCRPC combo): The most common treatment‑emergent adverse events considered related to mervometostat were diarrhea (42.6%), dysgeusia (42.6%), and anemia (36.2%). Grade ≥3 treatment‑related AEs occurred in 17.0%; no treatment‑related deaths were reported. Discontinuations due to AEs occurred in 19.1%. (ascopubs.org)
In the randomized dose‑expansion (mCRPC): The combination arm’s most frequent AEs were diarrhea (78%), decreased appetite (58.5%), and dysgeusia (58.5%); grade ≥3 TEAEs occurred in 53.7% vs 42.5% with enzalutamide alone. Exploratory work suggested that an 875 mg BID with‑food regimen provided similar exposure to 1250 mg BID fasting, with an improved safety profile; this regimen is used in phase 3. (ascopubs.org)
Pharmacodynamic/biopsy study: Demonstrated on‑target EZH2 inhibition without new specific safety signals beyond the combination experience. (ascopubs.org)

Active trials using Mervometostat

Found 4 active trials using this drug:

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Mevrometostat (PF-06821497) With Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer (MEVPRO-3)

Sponsor: Pfizer (industry) Phase: 3 Start date: Sept. 28, 2025

HealthScout AI summary: Men with metastatic castration-sensitive prostate adenocarcinoma (ECOG 0–1) who are ARPI- and chemotherapy-naïve in the mCSPC setting (allowing up to 3 months of ADT/first-generation antiandrogen) are randomized to enzalutamide plus the EZH2 inhibitor mevrometostat (PF-06821497) versus enzalutamide alone. Investigational agent mechanism: selective EZH2 (PRC2) inhibition to reduce H3K27 methylation and re-express silenced tumor suppressor genes.

ClinicalTrials.gov ID: NCT07028853

A PHASE 3, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED STUDY OF PF-06821497 (MEVROMETOSTAT) WITH ENZALUTAMIDE IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MEVPRO-2)

Sponsor: Pfizer (industry) Phase: 3 Start date: Oct. 22, 2024

HealthScout AI summary: Men with metastatic castration-resistant prostate adenocarcinoma (ECOG 0–1) who are ARSI- and abiraterone-naïve (prior docetaxel for mCSPC allowed if no early progression) are randomized to enzalutamide plus the EZH2 inhibitor mevrometostat (PF-06821497) vs enzalutamide alone. The investigational agent targets EZH2/PRC2 to reduce H3K27 methylation and potentially enhance antitumor activity; primary endpoint is rPFS.

ClinicalTrials.gov ID: NCT06629779

A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF PF-06821497 (MEVROMETOSTAT) IN COMBINATION WITH ENZALUTAMIDE COMPARED WITH ENZALUTAMIDE OR DOCETAXEL IN PARTICIPANTS WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER PREVIOUSLY TREATED WITH ABIRATERONE ACETATE (MEVPRO-1)

Sponsor: Pfizer (industry) Phase: 3 Start date: Oct. 21, 2024

HealthScout AI summary: Men with metastatic castration-resistant prostate cancer who progressed on abiraterone (no prior ARSI, limited prior chemo) are randomized to mervometostat (PF-06821497), an EZH2 inhibitor, plus enzalutamide versus physician’s choice of enzalutamide or docetaxel. Intended for ECOG 0–2, castration-resistant patients without small cell features or active CNS disease.

ClinicalTrials.gov ID: NCT06551324

A PHASE I DOSE ESCALATION AND EXPANDED COHORT STUDY OF PF 06821497 (MEVROMETOSTAT) IN THE TREATMENT OF ADULT PATIENTS WITH RELAPSED/REFRACTORY SMALL CELL LUNG CANCER (SCLC), CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND FOLLICULAR LYMPHOMA (FL)

Sponsor: Pfizer (industry) Phase: 1 Start date: April 17, 2018

HealthScout AI summary: This trial enrolls adults with relapsed or refractory small cell lung cancer, metastatic castration-resistant prostate cancer post-abiraterone/enzalutamide, or follicular lymphoma to receive mevrometostat, a selective oral EZH2 inhibitor, as monotherapy or in combination with standard of care therapies. Treatment assignment varies by disease type and prior therapy, with some arms randomizing mCRPC patients to mevrometostat plus standard of care versus standard of care alone.

ClinicalTrials.gov ID: NCT03460977